(102) Start High, Go Fast: Rapid Split-Dose Inpatient Methadone Titration in Pregnancy

Background & Introduction: Stabilization of pregnant people with opioid use disorder (OUD) on medications for opioid use disorder (MOUD) is critical, particularly in the fentanyl era, yet MOUD receipt during pregnancy remains low (1). MOUD use during pregnancy is safe and improves outcomes, while opioid withdrawal is associated with adverse perinatal outcomes (2). In the inpatient setting, untreated symptoms of opioid withdrawal are cited as a common reason for premature discharge (3). Prior studies have found rapid inpatient methadone titration to be associated with lower risk of premature discharge (4) and a rapid split-dose titration strategy to be feasible in a small sample of pregnant patients (5). Here, we report the safety and stabilization outcomes of symptom-driven, split-dose, rapid methadone titration in the largest reported sample to date of pregnant people who use fentanyl.

Methods: In this case series, we reviewed charts of pregnant patients admitted to our hospital-based, inpatient substance use treatment program between January 1 and December 31, 2024. Patients were included if they were pregnant, using fentanyl, opted to start MOUD with methadone, had not taken methadone in the prior 14 days, and were not in labor or postpartum at the time of admission. Our rapid methadone titration protocol recommended beginning with 30mg twice daily, plus 10mg as needed up to every four hours for patient complaints of withdrawal, not based on Clinical Opioid Withdrawal Scale (COWS) scoring. The protocol allows for flexibility based on clinician judgment and does not set daily dose limits. Short-acting opioids and ancillary medications for symptom management were available per clinician judgment but were not routinely prescribed. Patient demographics, gestational age on admission, total methadone received per day, methadone dose on day of discharge, and the day on which the last as-needed dose of methadone was given were extracted from the medical record. Charts were reviewed for adverse events including prolonged QT interval, sedation or respiratory depression requiring dose decrease or naloxone administration, preterm labor during methadone stabilization, and patient-initiated discharge prior to methadone stabilization.

Results: 77 admissions by 71 unique pregnant patients were included. The mean gestational age was 24 weeks on admission. The average dose of methadone received in the first 24 hours was 118mg (SD 36mg). 52 patients (68%) remained admitted until reaching a stable methadone dose and the average total daily dose at discharge was 212mg (SD 91mg). Three patients (6% of stabilized patients) stabilized at < 100mg, 21 (40%) between 100-199mg, 21 (40%) between 200-299mg, and 7 (13%) >300mg. Of 34 patients who received at least 200mg in a day, it took on average 7 days (SD 4) to reach 200mg/day. It took on average 10 days (SD 6) to be sufficiently stable to no longer require rapid titration, defined as the last day that as-needed methadone was given. Of the patients who did not complete stabilization, 17 (22%) self-discharged and 8 (10%) switched to buprenorphine. Four patients (5%) had preterm delivery during methadone stabilization. Two (3%) patients had QTc intervals >500ms, two (3%) had their dose reduced for respiratory depression, and four (5%) had their dose reduced for sedation. No patients required naloxone.

Conclusion & Discussion: Rapid, split-dose inpatient methadone titration in pregnancy was safe and resulted in high rates of completion of stabilization. Our patients received an average of 118mg of methadone in the first 24 hours of admission, the highest that has been reported in this population. The incidence of respiratory depression, QTc prolongation, and preterm delivery were low and no patients required naloxone. These outcomes suggest that removal of restrictions like daily dose limits and COWS score thresholds, paired with close monitoring and skilled nursing staff can safely facilitate rapid inpatient titration of methadone during pregnancy and may improve retention in treatment by reducing symptoms of withdrawal. Generalizability of our findings may be limited outside of a dedicated inpatient treatment program with nursing staff highly skilled in patient-centered withdrawal management. Limitations also include incomplete pregnancy outcome data for patients who delivered outside of our health system, and a lack of data on opioid treatment program (OTP) retention post-discharge.

References: 1. Cioffi CC, Acevedo AM, Cohen DJ, Kaufman MR, Parker K, Terplan M, Lindner SR. A cross-sectional study of differences in medication for opioid use disorder receipt among pregnant people enrolled in Medicaid in Oregon, United States. Addiction. 2025 May;120(5):997-1006.
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